*From the Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine and Division of Medical Genetics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN.

Extract

Primary pulmonary hypertension (PPH) is a progressive and fatal
disease caused by proliferative occlusion of the smallest pulmonary
arteries. It can occur at any age in either gender. PPH has also been
recognized as a genetic disease, transmitted in an autosomal dominant
manner. Mutations in the gene encoding the bone morphogenic protein
receptor II (BMPRII) have been shown to be the molecular basis of
familial PPH. BMPRII is a member of the transforming growth
factor-β–receptor II family. Mutations in 12 of the 13 exons of
BMPRII have been recognized but all produce a similar outcome, PPH.
Using stable transfection of normal mouse mammary gland epithelium
cells, we show that mutations in the different functional domains of
BMPRII are capable of eliciting different biochemical phenotypes.
Stable cell lines expressing wild-type or mutant BMPRII constructs were
assayed for luciferase expression driven from a SMAD binding
element-responsive promoter. The mutations constructed were those
detected in PPH kindreds. Native cells express 11 times more luciferase
after stimulation with the ligand bone morphogenic protein 4. Kinase
domain mutations produced twice as much luciferase as the controls at
baseline and expressed four times more than the baseline levels with
stimulation with bone morphogenic protein 4. The cytoplasmic tail
mutation expressed similar amounts of luciferase at baseline as the
wild type but increased more than six times with stimulation. These
data suggest that mutations in specific BMPRII domains affect bone
morphogenic protein signaling differently in the presence or absence of
ligand.

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